Sex and Gender Differences in Chronic Kidney Disease—Explained by the Brenner–Luyckx Concept of Hyperfiltration

At the beginning of life, there are no sex differences in fetal kidney growth, nephron endowment nor in the prevalence of low birth weight. In chronic kidney disease (CKD) in adults, however, significant sex- and gender-specific differences exist in diagnosis, progression, and management of CKD. In adult individuals, CKD is more prevalent in women, but CKD progression is faster in men; nevertheless, women have a higher life expectancy than men. A possible explanation for the enigmatic higher CKD prevalence in women may derive from the Brenner-Luyckx concept of hyperfiltration. Diseases that lead to hyperfiltration will lead to premature nephron loss and to a faster decline in glomerular filtration rate (GFR). This condition is predominantly seen in middle-aged men with a higher GFR, larger hypertrophied kidneys, and a higher prevalence of arterial hypertension, diabetes mellitus, smoking, and hypercholesterolemia compared to women. Thus, a high GFR may not be a good sign if it reflects hyperfiltration. Any GFR must be interpreted against the comorbidities of an individual. An individual may end up with a realistic GFR far below normal once hyperfiltration is stopped, for example, by a Sodium Glucose-Linked Transporter 2 (SGLT2) inhibitor. With regard to the management of CKD, women with CKD receive poorer healthcare compared to men with CKD. Women less frequently receive a CKD diagnosis, are less frequently referred to nephrology for co-management, less frequently undergo eGFR and albuminuria assessments, and are less likely to receive guideline-recommended treatments for CKD, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and statins. Cardiovascular risk factors are less rigorously controlled in women with CKD compared to men with CKD. The causes for the poorer CKD care among women are to be found in gender rather than in sex. It is crucial to integrate assessments of sex and gender into both clinical routines and scientific reports. All studies should incorporate sex- and gender-specific analyses, and the evaluation of pre- and postmenopausal women should be conducted separately. The utilization of Gender Scores can help identify the impact of cultural, societal, and psychological factors on observed gender differences in ambulatory healthcare for those with CKD. Guidelines need to be sensitive to gender and emphasize the existing knowledge gaps regarding sex and gender differences in CKD healthcare. Urgent attention is required to substantially improve and ensure equitable healthcare for CKD across sexes and genders.